Memory Enhancement by A Genetic Increase in cAMP Signals

通过 cAMP 信号的遗传增强增强记忆

• 批准号: 7048100
• 负责人: DANIEL R STORM
• 金额: $ 33.04万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7048100
• 关键词: AMPA receptors; G protein coupled receptor kinase; adenylate cyclase; biological signal transduction; cAMP response element binding protein; calcium; chromosome translocation; cyclic AMP; gene expression; genetic regulatory element; genetic transcription; genetically modified animals; laboratory mouse; memory; memory disorders; mitogen activated protein kinase; phosphodiesterases

DESCRIPTION (provided by applicant): Several human diseases including Alzheimer's and Rubinstein-Taybi syndrome are characterized by memory defects. The development of drugs to enhance the memory of compromised patients could have a major impact on the quality of life for these patients and others with memory defects. Evidence from several labs indicates that memory in mice may be enhanced using inhibitors of cyclic nucleotide phosphodiesterases (PDEs) to increase cAMP in the brain. Another promising drug target site to increase cAMP specifically in the brain is AC1, a neurospecific adenylyl cyclase that it is stimulated by activity-dependent calcium increases. To test this idea genetically, we made mice overexpressing AC1 in the hippocampus using the Ipha-CaM Kinase II promoter. These transgenic mice (AC1+) show enhanced LTP and memory for novel objects as well as a reduced rate of contextual memory extinction. Preliminary data indicate that the gain in memory may be due to enhanced signaling through the MAPK pathway. These data suggest the interesting possibility that AC1 may be a pharmacological "window of opportunity" to enhance memory formation. The major objective of this grant is to determine why AC1+ mice have superior memory. We hypothesize that AC1+ mice show memory enhancement because of the unique regulatory properties of AC1 which include its calcium sensitivity and synergistic activation by Gs-coupled receptors and calcium. We hypothesize that AC1+ mice show superior memory for novel objects because of more robust training- induced CRE-mediated transcription. This may be due to training-induced amplification MAPK activity, MAPK nuclear translocation, or postsynaptic depolarizations. We also propose that genetic enhancement of AC1 activity in the brain may overcome memory defects associated with Rubinstein-Taybi syndrome, a genetic disease due to a truncated form of the CREB binding protein (CBP).

描述（由申请人提供）：包括阿尔茨海默氏症和鲁宾斯坦 - 塔比综合症在内的几种人类疾病的特征是记忆缺陷。为增强受损患者的记忆的药物的开发可能会对这些患者和患有记忆缺陷的其他人的生活质量产生重大影响。来自几个实验室的证据表明，使用环状核苷酸磷酸二酯酶（PDES）的抑制剂可以增强小鼠的记忆，以增加大脑的cAMP。另一个有前途的药物靶位部位特别增加了大脑中的cAMP，这是AC1，这是一种神经特异性腺苷酸环化酶，它受到活性依赖性钙的增加而刺激。为了从遗传上测试这一想法，我们使用IPHA-CAM激酶II启动子在海马中使小鼠过表达AC1。这些转基因小鼠（AC1+）显示出增强的LTP和新颖对象的存储器，以及降低的上下文记忆灭绝率。初步数据表明，内存的增益可能是由于通过MAPK途径增强的信号传导所致。这些数据表明，AC1可能是增强记忆形成的药理“机会之窗”的有趣可能性。该赠款的主要目的是确定为什么AC1+小鼠具有较高的记忆力。我们假设AC1+小鼠显示出记忆力增强，因为AC1具有独特的调节特性，包括其钙敏感性和通过GS耦合受体和钙的协同激活。我们假设AC1+小鼠由于更强大的训练诱导的CRE介导的转录而显示出新的对象的出色记忆。这可能是由于训练引起的扩增MAPK活性，MAPK核易位或突触后去极化。我们还提出，大脑中AC1活性的遗传增强可能会克服与鲁宾斯坦 - 塔比综合征相关的记忆缺陷，鲁宾斯坦 - 塔比综合症是由于CREB结合蛋白（CBP）的截短形式引起的遗传疾病。